The present invention relates to an eye drop comprising a xcex2-blocker and a C3-C7 fatty acid or the salt thereof. Also, the present invention relates to a method to promote penetration of a xcex2-blocker into the eye and to improve the retention of the xcex2-blocker in the ocular tissues by incorporating a C3-C7 fatty acid or the salt thereof into an eye drop containing the xcex2-blocker.
Recently, the xcex2-blockers, such as carteolol hydrochloride, timolol maleate, betaxolol hydrochloride and the like, are used as a medicine for glaucoma in the form of the eye drop. However, many of the active components of the eye drops such as carteolol hydrochloride have high water-solubility, and in these cases, the highly hydrophobic corneal epithelium becomes a barrier to the penetration of the components into the eye. It is therefore necessary to instill the eye drop containing the components in high dose or many times in order to get the sufficient amount of the components penetrated in the eye tissues for lowering an intraocular pressure. However, in order to separate from the systemic effect of the xcex2-blocker, to get more effect on lowering intraocular pressure and to get the prolonged-action of the xcex2-blocker, it is preferable to promote penetration of the drugs into the eye and to prolong retention of the drug in the eye than to instill a high dose of the eye drop and to instill many times.
From the above view point, it has been investigated to improve the permeability of the xcex2-blocker into cornea, and it is reported that capric acid (C10 saturated fatty acid) promotes the permeability of the xcex2-blocker such as atenolol, carteolol, tilisolol and timolol into cornea in vitro (H. Sasaki et al., Pharm. Research. 12(8), 1146-1150 (1995)) and that the instillation of the eye drop containing ion pair of caprylic acid (C8 saturated fatty acid) and timolol to a rabbit increases the amount of timolol penetrated into aqueous humor (M. R. Gasco et al., J. Pharm. Biomed. Anal. 7, 433-439 (1989)). JP Patent No. 2563336 also discloses that bunazosin hydrochloride of a sympathetic xcex11 receptor blocker can enhance the permeability into cornea by incorporating caproic acid, caprylic acid and capric acid (C6-C10 linear fatty acids).
However, in the prior art, it can not be found any data or any description showing that the retention time of the xcex2-blocker or the sympathetic xcex11 receptor blocker in the ocular tissues is prolonged, but only the descriptions of the promotion of the drug penetration into cornea and the increase of the amount of the drug permeated in aqueous humor.
On the other hand, sorbic acid of C6 unsaturated fatty acid is a compound commonly used as a preservative of agents for a contact lens because of its becteriostatic effect. However, there is no report showing that the unsaturated fatty acid such as sorbic acid accelerates the penetration of the drugs into the eye by the instillation of the eye drop, but on the contrary, there has been reported that the acid has no effect on the corneal permeability of tilisolol of the xcex2-blocker in vitro (J. Pharm. Pharmacol. 47, 703-707 (1995)). There is also no prior art concerning the effect of the C3-C7 fatty acids on the corneal permeability of the xcex2-blocker.
The object of the present invention is to provide an eye drop capable of promoting the penetration of a xcex2-blocker such as carteolol hydrochloride, timolol maleate and betaxolol hydrochloride, and to improve the retention of the drug in the ocular tissues.
Herein, the penetration into the eye means that the drug after the instillation permeates into corneal epithelium and the like and penetrates into the ocular tissues such as corneal stroma, aqueous humor, iris and ciliary body, lens, vitreous body and retina.
As the results of the extensive studies by the present inventors, it was found that the sorbic acid which does not show any action promoting the permeation of the xcex2-blocker into cornea in vitro promotes the amount of penetration of the xcex2-blocker in vivo and prolongs the retention period of xcex2-blocker in the ocular tissues. Furthermore, it was also found that the C3-C7 fatty acid accelerates the penetration of xcex2-blocker into the eye, thence the present invention was accomplished.
Namely, the present invention relates to
(1) an eye drop comprising a xcex2-blocker and a C3-C7 fatty acid or the salt thereof,
(2) the eye drop according to (1), wherein the xcex2-blocker is carteolol or the salt thereof,
(3) the eye drop according to (1), wherein the xcex2-blocker is timolol or the salt thereof,
(4) the eye drop according to (1), wherein the xcex2-blocker is betaxolol or the salt thereof,
(5) the eye drop according to one of (1) to (4), wherein the C3-C7 fatty acid is an unsaturated fatty acid,
(6) the eye drop according to one of (1) to (5), wherein the C3-C7 fatty acid is a C6 unsaturated fatty acid,
(7) the eye drop according to (6), wherein the C6 unsaturated fatty acid is sorbic acid,
(8) a method for promoting the penetration of a xcex2-blocker into the eye and improving the retention of the xcex2-blocker in the ocular tissues which comprises incorporating a C3-C7 fatty acid or the salt thereof into an eye drop containing the xcex2-blocker.
As the xcex2-blocker used for the eye drop of the present invention, for example, carteolol, timolol, betaxolol, befunolol, metipranolol, levobunolol and the like which are used as a medicine for glaucoma may be used. Among them, carteolol, timolol and betaxolol may be used preferably.
As the pharmaceutically acceptable salt of the xcex2-blocker used for the eye drop of the present invention, there are exemplified by acid addition salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, acetate, maleate, fumarate, citrate and tartrate. Among the above salts, hydrochloride and maleate are preferable.
The concentration of the xcex2-blocker or the salt thereof (hereinafter, may be simply called as xe2x80x9cthe xcex2-blockerxe2x80x9d) used for the eye drop of the present invention is different depending on the degree of glaucoma, but may be usually about 0.02 to 3 w/v %, preferably about 0.05 to 2 w/v %, more preferably about 0.1 to 2 w/v %.
The C3-C7 fatty acid (hereinafter, may be simply called as xe2x80x9cthe fatty acidxe2x80x9d), preferably the C4-C6 fatty acid may be used for the eye drop of the present invention. The fatty acid used in the present invention may be one of a straight or a branched and a saturated or an unsaturated monocarboxylic acid and dicarboxylic acid, preferably propionic acid, butyric acid, isobutyric acid, valeric acid, pivalic acid, caproic acid, heptanoic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, crotonic acid, sorbic acid, maleic acid, fumaric acid and the like, more preferably sorbic acid. As the salt of the fatty acid, there are exemplified by sodium salt, potassium salt and the like.
The concentration of the fatty acid or the salt thereof used for the eye drop of the present invention is different depending on the kind of xcex2-blocker, but may be usually about 0.01 to 10 w/v %, preferably about 0.02 to 5 w/v %, more preferably about 0.04 to 2 w/v %. In the ratio of the fatty acid or the salt thereof to the xcex2-blocker, the fatty acid or the salt thereof may be usually 0.01 to 10 weight ratio, preferably 0.05 to 3 weight ratio, more preferably 0.1 to 5 weight ratio, relative to 1 weight of the xcex2-blocker. Also, the ratio of the fatty acid or the salt thereof may be 0.2 to 5 moles, preferably 0.2 to 2 moles, relative to 1 mole of carteolol hydrochloride, may be 0.2 to 10 moles, preferably 1 to 5 moles, relative to 1 mole of timolol maleate, and may be 0.5 to 10 moles, preferably 2 to 5 moles, relative to 1 mole of betaxolol hydrochloride.
pH of the eye drop of the present invention may be adjusted usually to 4.5 to 8.5, preferably 5 to 8, more preferably 6 to 7.
To the eye drop of the present invention, additives usually used for the eye drop, for example, isotonic agents (sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose and propylene glycol, etc.), buffer (phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamic acid and xcex5-aminocaproic acid, etc.), preservatives (benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, parahydroxybenzoates, sodium edetate and boric acid, etc.), stabilizers (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid and dibutylhydroxytoluene, etc.), thickening agents (water-soluble cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose; sodium chondroitin sulfate, sodium hyaluronate, carboxyvinylpolymer, polyvinyl alcohol, polyvinylpyrrolidone and macrogol, etc.), pH adjusters such as hydrochloric acid, sodium hydroxide, phosphoric acid and acetic acid may be added, if desired. The amount of the additives is different depending on the kind of the additives and the purpose thereof, but may be a concentration capable of accomplishing the purpose thereof. The isotonic agents may be usually added in an amount to give 0.8 to 1.2 of the osmotic pressure ratio. The buffers may be added in an amount of about 0.01 to 2 w/v %. The stabilizers may be added in an amount of about 0.001 to 1 w/v %. And the thickening agents may be added in an amount of about 0.001 to 3 w/v %.
To the eye drop of the present invention, other pharmaceutical components other than the xcex2-blocker may be appropriately added not so far as the object of the present invention is deviated.
The eye drop of the present invention may be produced according to the usual method for producing the eye drop, for example, a method described in Ophthalmic Solutions of General Rules for Preparations (JP, 13th edition).
Because the eye drop of the present invention promotes the penetration of the xcex2-blocker into the eye and improves the retention of the xcex2-blocker in the ocular tissues, the frequency of the instillation can be decreased and the bother in instilling many times can be avoided. The sufficient effect is obtained also when the incorporated amount of the drug is decreased. Concretely, for example, in case that the eye drop containing carteolol hydrochloride 1 w/v % is used for the adult patient suffering from glaucoma, it may be instilled once about 1 drop per 1 to 3 days, preferably once about 1 drop per 1 day. In case that timolol maleate 0.68 w/v % (0.5 w/v % as timolol) is employed, the eye drop may be instilled once about 1 drop per 1 day.